Pathogenesis of Liver-Dependent Acute Lung Injury

描述（由申请方提供）：肝功能和急性肺损伤之间存在联系：a）在肝衰竭的情况下，ARDS几乎是一致致命的; B）在ARDS患者中肝功能障碍很常见; c）动物研究表明，促炎细胞因子在内毒素血症或肝缺血时从肝脏释放。在原位灌注的猪制备中，我们发现内毒素诱导的肺损伤仅在肝脏被包括在循环中时发生。我们的结论是，内毒素不会直接损伤肺，而是通过内毒素诱导的肝脏介质释放来“准备”肺损伤。我们假设：B）内毒素血症诱导编码分泌到循环中的蛋白质的基因的肝表达增加，所述蛋白质介导肝依赖性肺损伤，c）骨髓来源的干细胞是肝和肺中对内毒素血症的急性炎症反应的关键调节剂; d）骨髓细胞对内毒素诱导的急性炎症和肺损伤的抑制主要是非造血间充质样干细胞亚群的作用。1）确定肺损伤的内毒素“引发”是否是由内毒素诱导的介质从肝脏释放引起的损伤所必需的，确定肺和肝脏中对内毒素血症的分子应答，并鉴定在肝脏中产生并释放到介导肺损伤的循环中的内毒素诱导的介质; 2）确定骨髓来源的细胞对内毒素诱导的炎症的影响（肺和肝）和肝脏释放介质，表征这些细胞对内毒素诱导的分子应答的作用，确定是否必须将骨髓细胞递送至肺和肝以防止肺损伤，并确定有效的骨髓衍生细胞群是否是非造血的和间充质样的;和3）体内确定接近扩增的骨髓细胞库对内毒素诱导的炎症和肺损伤的影响，并表征在异种小鼠制备物中内毒素血症后体内募集到肺和肝的细胞群。这些研究将阐明急性肺部炎症和损伤的机制，并确定新的治疗潜力。

DESCRIPTION (provided by applicant): There are connections between hepatic function and acute lung injury: a) ARDS in the setting of hepatic failure is almost uniformly fatal; b) hepatic dysfunction is common in patients with ARDS; and c) animal studies demonstrate release of pro-inflammatory cytokines from the liver in response to endotoxemia or hepatic ischemia. In an in situ perfused swine preparation we find that endotoxin induced lung injury only occurs when the liver is included in the circulation. We conclude that endotoxin does not injure the lung directly, but "primes" the lung for injury that is mediated by endotoxin induced release of mediators from the liver. We hypothesize that: a) Direct effects of endotoxin prime the lung for injury, but injury requires mediators released from the liver; b) Endotoxemia induces increased hepatic expression of gene(s) encoding protein(s) secreted into the circulation that mediate liver dependent lung injury, c) Bone marrow derived stem cells are critical modulators of the acute inflammatory response to endotoxemia in both the liver and the lungs and; d) Suppression of endotoxin induced acute inflammation and lung injury by bone marrow cells is primarily an effect of a subset of non-hematopoietic, mesenchymal-like stem cells. We will test these hypotheses by: 1) Determining whether endotoxin "priming" of the lung for injury is necessary for injury caused by endotoxin induced release of mediators from the liver, determining molecular responses to endotoxemia in both the lungs and liver and identifying endotoxin induced mediators produced in the liver and released into the circulation that mediate lung injury; 2) Determining effects of bone marrow derived cells on endotoxin induced inflammation (lung and liver) and release of mediators by the liver, characterizing effects of these cells on endotoxin induced molecular responses, determining whether bone marrow cells must be delivered to both the lungs and the liver to prevent lung injury, and determining whether the population of effective marrow derived cells is non-hematopoietic and mesenchymal-like; and 3) Determining in vivo the effects of access to an expanded pool of bone marrow cells on endotoxin-induced inflammation and lung injury and characterizing the populations of cells recruited to the lungs and the liver in vivo following endotoxemia in a parabiotic mouse preparation. These studies will elucidate mechanisms of acute lung inflammation and injury and identify novel potentials for therapy.